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(Circulation. 1997;96:1074-1077.)
© 1997 American Heart Association, Inc.

Articles

Glucose-Insulin-Potassium in Acute Myocardial Infarction

The Time Has Come for a Large, Prospective Trial

Carl S. Apstein, MD; ; Heinrich Taegtmeyer, MD, DPhil

From the Boston University School of Medicine (C.S.A.), Boston, Mass, and The University of Texas–Houston Medical School (H.T.).

Correspondence to Carl S. Apstein, MD, Boston University School of Medicine, Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute (Rm W-611), 80 E Concord St, Boston, MA 02118 () or Heinrich Taegtmeyer, MD, DPhil, University of Texas–Houston Medical School, Internal Medicine/Cardiology, 6431 Fannin St (Rm 1.246 MSB), Houston, TX 77030. e-mail capstein{at}bu.edu

Key Words: Editorials • myocardial infarction • glucose • insulin • potassium

	Introduction

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
An important but nearly forgotten therapy for reducing mortality in acute MI has been reexamined and reported in this issue of Circulation.¹ After performing a meta-analysis, Fath-Ordoubadi and Beatt came to the remarkable conclusion that glucose-insulin-potassium (GIK) had reduced in- hospital acute myocardial infarction (MI) mortality by 28% in nine prior clinical trials involving 1932 patients and by 48% in four studies in which GIK was administered at high concentrations to maximally suppress plasma free fatty acid (FFA) levels. This magnitude of mortality reduction is comparable to that achieved with thrombolytic therapy² and supports the concept that metabolic protection of ischemic myocardium may be as important as reperfusion itself. However, the strength of this conclusion has the intrinsic weaknesses and limitations of the meta-analysis technique. In addition, all of the cited studies were done in the prethrombolytic era.

Before GIK can be considered as adjunctive therapy to revascularization in acute MI, confirmatory results are required from a modern, large-scale, prospectively randomized trial with adequate statistical power. Because urgent reperfusion, through thrombolytic therapy or primary angioplasty, is standard care for acute MI, the next target for therapeutic interventions is the myocardium. Restoration of blood flow and oxygen supply to the ischemic myocardium is critical but may not fully exploit the potential for salvage. Therefore, any trial of GIK should assess its value as an adjunctive agent to (1) delay cell death until reperfusion can occur and (2) optimize energy transfer in the postischemic heart.

	Recent Related Studies

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
We believe that cautious optimism is justified regarding the outcome of such a trial because abundant experimental and clinical evidence suggests that GIK may be more potent in a setting of ischemia and reperfusion than during ischemia alone. The value of myocardial metabolic support with GIK has been demonstrated in the ischemia/reperfusion setting of cardiac surgery.^{3 4} In experimental studies, the protective effects of a high glucose and insulin substrate were much more apparent after reperfusion than during the preceding ischemic period,⁵ suggesting that GIK may slow the rate of development of ischemic necrosis and expand the time during which reperfusion therapy can salvage ischemic myocardium, as well as the amount of salvage that is achieved. In a recent small, nonrandomized study from a community hospital north of Boston, GIK was given as adjunctive therapy (together with carnitine and magnesium) to 44 patients with acute MI who were also treated with thrombolysis. The patients receiving the metabolic support plus thrombolysis had a significantly lower end point incidence of "death or heart failure development" than historical control patients treated with thrombolysis without concomitant metabolic support.⁶ In the Swedish DIGAMI trial⁷ of diabetic patients with acute MI, half received thrombolysis with streptokinase and were randomized to receive glucose plus insulin infusions followed by multidose insulin therapy or to receive standard care. In the glucose-plus-insulin group, there was a trend to a decrease in mortality at 3 months, which became significant at 1 year (29% relative mortality reduction, P=.027). The effect of glucose plus insulin was most pronounced in patients without prior insulin use and at low cardiovascular risk; in this subgroup, the in-hospital mortality was reduced by 58% (P<.05), and the 1-year mortality rate was reduced by 52% (P<.02). None of these studies provides definitive evidence for a beneficial effect of GIK in combination with revascularization therapy of acute MI, but together with the meta-analysis of Fath-Ordoubadi and Beatt,¹ they strongly suggest the value of such therapy and provide a strong rationale for a definitive prospective trial to resolve this issue.

	Energy Metabolism of Acutely Infarcting and Reperfused Myocardium

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
With the advent of thrombolytic therapy for acute MI and the reperfusion of previously ischemic myocardium, the general concept of metabolic support for the heart deserves to be reexamined in the light of newer concepts of energy transfer in heart muscle. In the large majority of patients with acute MI, the acutely infarcting region has significant collateral flow⁸ such that this region has a heterogeneous mixture of anaerobic and oxidative metabolism occurring concomitantly. Furthermore, the biochemical features of the postischemic myocardium (ie, MI after thrombolysis) differ from the biochemical features of the ischemic myocardium. Therefore, the effects of GIK on energy transfer should be considered for both anaerobic and oxidative pathways.

The magnitude of myocardial energy transfer is best illustrated by the simple calculation that the human heart, which weighs 300 g, produces and uses 5 kg ATP over 24 hours. The energy is derived from the oxidation of fatty acids, glucose, lactate, ketone bodies, and even amino acids. In addition to these substrates, heart muscle uses, under defined circumstances, some of its endogenous substrates, glycogen and triglycerides.

We propose that in the normal, well-oxygenated heart, efficient energy transfer requires simultaneous oxidation of several substrates through a series of moiety-conserved cycles. Not all substrates are created equal, and the interplay of different energy-providing fuels underpins normal contractile function of the heart.⁹ Lack of oxygen and the accumulation of metabolic products profoundly change this interactive transfer of energy. Anaerobic glycolysis becomes the predominant source for a limited amount of ATP, which may or may not suffice to support the most essential cellular functions.

Just as the causes of myocardial ischemia are diverse, so are the cellular responses to myocardial ischemia and reperfusion. The latter include the cessation of the metabolism of substrates feeding reducing equivalents into the respiratory chain, production of partially reduced oxygen species (especially superoxide hydrogen peroxide radicals), uncoupling and inhibition of electron transport, increased cytosolic Ca²⁺ levels, loss of adenine nucleotide translocase activity, reversal of mitochondrial ATPase activity, loss of mitochondrial antioxidant defenses, and loss of mitochondrial and cytosolic enzymes. In addition, glycogen and key intermediates of the citric acid cycle are lost.⁹ Reperfusion may worsen the damage caused by oxygen-derived free radicals. Although fatty acid oxidation rapidly normalizes in reperfused hearts, the oxidation of glucose remains depressed, as does contractile function.¹⁰

	Metabolic Substrates as Therapy

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
Agents that alter energy substrate metabolism in the ischemic and reperfused heart offer an exciting new modality for the treatment of ischemic heart disease. Traditionally, severe heart failure caused by acute myocardial ischemia is managed by the combined use of pharmacological (positive inotropic) agents and mechanical interventions that improve coronary flow and/or cardiac output (intra-aortic balloon counterpulsation or left ventricular unloading). Although metabolic protection against ischemic/reperfusion injury has been a cornerstone of successful strategies of myocardial preservation during cardiac surgery, cytoprotective metabolic strategies have not generally been extrapolated to the acute MI setting. Yet, the treatment of acute MI with metabolic interventions such as GIK has also had a long but inadequately appreciated history.

	Mechanisms of the Protection by GIK of Ischemic Myocardium

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
More than 35 years ago, Sodi-Pallares¹¹ reported that the systemic administration of a solution of GIK ("polarizing solution") shortened the ECG evolution of an acute MI, reduced the incidence of ventricular ectopy activity, and improved the early survival in acute MI. This early use of GIK was based on a sound rationale: insulin stimulates K⁺ reuptake through stimulation of the Na⁺,K⁺-ATPase while it stimulates glucose uptake for glycolytic energy production.

More recent work has identified additional mechanisms by which GIK is protective of ischemic myocardium. In the setting of experimental low-flow ischemia, a high level of glucose and insulin has been shown to improve ischemic and postischemic myocardial systolic and diastolic function as well as coronary vasodilation, thereby potentially decreasing the "no-reflow" phenomenon.⁵ The increased amount of available glycolytic substrate increased glycolytic flux and glycolytic ATP synthesis, attenuated the ischemia-induced decrease in ATP and phosphocreatine levels, and prevented the increase in inorganic phosphate.^{12 13} The prevention of the ischemia-induced increase in inorganic phosphate resulted in preservation of a higher calculated free energy yield from all ATP hydrolysis, not only from glycolytically derived ATP. High glucose and insulin and an increased glycolytic flux may also increase pyruvate generation, which in turn provides substrate for anaplerotic reactions and preserves all moieties of the citric acid cycle.⁹ Glycolytic ATP protects membranes,¹⁴ drives the transport of Ca²⁺ into the sarcoplasmic reticulum,¹⁵ and improves sodium homeostasis of ischemic myocardium.¹⁶

The provision of glucose and insulin also preserves and restores myocardial glycogen stores. Glycogen is rapidly mobilized during ischemia. Reduced glycogen concentrations impair force development, Ca²⁺ release, and contractile function.¹⁷ A positive correlation among enhanced glucose uptake, glycogen levels, and contractile function has been shown in patients undergoing revascularization for coronary artery disease.¹⁸

	Interaction of GIK With FFAs and Heparin

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
Increased (nonesterified) FFA levels have been shown to be toxic to ischemic myocardium and are associated with increased membrane damage, arrhythmias, and accelerated functional deterioration. Highly important GIK effects are to decrease both circulating FFA levels and myocardial FFA uptake.¹⁹ FFA levels are commonly increased in the patient with acute MI secondary to increased plasma catecholamine levels and to the effects of heparin. Although the antithrombotic effects of heparin are well known, usually little attention is paid to the action of heparin to activate lipoprotein lipase and markedly increase circulating FFA levels.²⁰ Because of its anti-FFA actions, GIK is likely to be of particular value in patients who receive heparin, which is one of the drugs most often administered after an MI.

	Role of GIK in Postischemic Myocardium

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
In the postischemic myocardium, there is an imbalance between glycolysis and glucose oxidation. It has been argued that postischemic contractile dysfunction is caused by impaired glucose oxidation and cytosolic proton accumulation, and agents that enhance glucose oxidation in the postischemic heart have also improved contractile dysfunction.²¹

We have also proposed that the depletion of glycogen stores and citric acid cycle intermediates is a major cause for impaired energy transfer in reperfused hearts.⁹ The replenishment of the glycogen pool and of the citric acid cycle occurs through anaplerosis. In heart muscle, a major source of anaplerosis of the citric acid cycle is the carboxylation of pyruvate. Because glucose is a direct precursor of pyruvate and pyruvate provides both substrates for the citrate synthase reaction (acetyl-CoA and oxaloacetate), it is easy to envision GIK as a metabolic substrate that provides a "jump start" for a collapsed system of energy transfer in the postischemic heart. This does not mean that glycolysis itself is unimportant in ischemia/reperfusion transitions. In isolated, working hearts made ischemic and then reperfused, glycolysis is a highly adaptive emergency mechanism that can prevent deleterious myocyte deenergization during forced ischemia/reperfusion transitions in the presence of excess oxidative substrate.²² Furthermore, in a similar model of ischemia and reperfusion, the inotropic and metabolic effects of insulin and epinephrine were additive and resulted in improved functional recovery in association with enhanced glucose uptake and utilization.²³ Thus, the different rationales for the use of metabolic support of the heart during both ischemia and reperfusion complement each other.

	The Long History of GIK

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 
The slow recognition of the potential usefulness of GIK for the treatment of acute MI is distressingly reminiscent of the sad history of the use of streptokinase for thrombolytic therapy. First introduced in the late 1950s, streptokinase was not finally appreciated until three decades and many deaths from acute MI later.

The use of GIK in acute MI has been inhibited by concerns that GIK could starve the cell of energy (glucose phosphorylation requires ATP) and worsen ischemic injury by worsening myocardial acidosis as a result of increased lactate production.²⁴ These concerns have been alleviated by recent studies showing that collateral flow exists in the acute infarct region of the large majority of patients at a level 15% of the perfusion level in the non-MI region⁸ ; such a level of coronary flow is adequate to wash out myocardial lactate and prevent the action by lactate to inhibit glycolysis.⁵ Direct measurements of ATP content and intracellular pH during such a degree of low-flow ischemia have shown that a high glucose-plus-insulin substrate increases ATP levels and does not worsen tissue acidosis (Reference 13¹³ and A.C. Cave, J. Friedrich, J.S. Ingwall, C.S. Apstein, and F.R. Eberli, Creatine Kinase Reaction and Other ATP Synthesis Pathways During Low-Flow Ischemia: Influence of Increased Glycolytic Substrate, submitted manuscript, 1997), an observation consistent with the analysis that during ischemia, proton generation from the hydrolysis of ATP far exceeds that contributed by lactate.²⁵

The potential use of GIK has also been delayed by a pharmaceutical industry that is indifferent to sponsoring research on therapy without the possibility of patents and profits. We have often wondered how rapidly GIK might have been developed, or at least have been tested in a large modern clinical trial, had there been any commercial interest.

The large number of conflicting and inconclusive prior clinical trials of GIK for acute MI has contributed importantly to the general lack of enthusiasm for its use. Fath-Ordoubadi and Beatt¹ performed a great service by reviewing these studies, discarding those in which small amounts of GIK were given or therapy was initiated too late to be useful, and summating the randomized trials in which adequate doses were given and therapy was initiated early; these studies were well planned but were terminated before any reached adequate statistical power to definitively test the GIK hypothesis. Their aggregate results suggest a statistically significant benefit of GIK that no single study could conclude.

We have also heard the argument that GIK therapy is "not worth it" because thrombolytic therapy has reduced the acute MI mortality rate to such low levels that further reductions via adjunctive agents would be difficult to achieve and prove statistically. Hence, it might not be worth the trouble of monitoring blood glucose and electrolyte levels every 6 hours. This argument is weak because frequent blood samples are already required to be obtained for diagnostic purposes. Most important, one must consider the large number of MIs that occur each year: 1.5 million in the United States alone. If the use of GIK can save 49 lives per 1000 cases,¹ then 75 000 lives could be saved annually in the United States through the use of this simple, safe, and synergistic therapy. Surely, this therapeutic potential warrants a definitive clinical trial before too many more years go by!

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Recent Related Studies Energy Metabolism of Acutely... Metabolic Substrates as Therapy Mechanisms of the Protection... Interaction of GIK With... Role of GIK in... The Long History of... References

 

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